This multidisciplinary SCOR is devoted to the study of the mechanisms of chronic or persistent pain with specialized focus on 1) sex-related factors that influence pain, and 2) painful clinical conditions that demonstrate a high prevalence in women. The Center's research program is diverse, and ranges from molecular studies to systems physiology studies to clinical studies. Our working model is that research on pain has clearly shown that a person's sex is an important factor in determining their perception of, and response to, painful stimulation and pathological pain. Several physiological and psychological mechanisms have been proposed to account for these sex differences, yet many hypotheses remain to be adequately tested. This SCOR would direct its efforts to evaluating physiological models of sex-related pain differences, including the influence of gonadal hormones. Additionally, this Center would evaluate pathophysiological models of chronic pain conditions that are more prevalent in women, focusing on temporomandibular joint disorders (TMD) and the visceral pain associated with conditions such as irritable bowel syndrome (113S). This Center would facilitate the transfer of basic scientific knowledge to the study of persistent pain in humans, and ultimately to the development of new methods of diagnosing and treating these conditions in the general population. One clinical and two basic science projects constitute the scientific basis of the application. The two principal objectives of this SCOR are: 1) To elucidate the underlying mechanisms associated with sex differences in persistent pain of deep muscle and visceral origin. Human and animal studies will explore hypothesized physiological mechanisms of sex differences in pain, including opioid receptor expression, peripheral nociceptor sensitivity, CNS sensitization, and CNS ascending/descending modulation, as well as the influence of gonadal steroids on these mechanisms. All three projects address this objective. 2) To explore the neural basis of temporomandibular disorder (TMD) pain, with special emphasis upon sex-related hypotheses. TMD is the major persistent orofacial pain condition of deep tissue origin. It shows a large prevalence in women of childbearing age. The pathophysiology of TMD is poorly understood, but several hypotheses based on sex-related factors have been proposed. Two of the proposed projects (#1and #3) direct efforts explicitly to evaluate such hypotheses.